COPD is the fourth leading cause of death in US and its global public health impact is destined to further increase worldwide. COPD is characterized by an inflammatory response to noxious agents (such as smoking) that originates in the airways but, in the long-term, may extend beyond the lung and contribute to the morbidity and mortality burden associated with this disease. To date, the temporal relationship between systemic inflammatory protein expression and COPD inception has not been resolved and whether systemic inflammation is causally linked to COPD development or it is simply a consequence of the disease remains to be determined. In this proposal, we aim at determining whether serum levels of inflammatory cytokines (IL-6, IL-8, TNF-alpha) and acute phase reactants (CRP, sCD14, and LBP) predict development of COPD among smokers and, once the disease has occurred, its clinical progression and mortality risk (Specific Aim 1). Because endotoxin exposure may contribute to initiate and sustain pulmonary and systemic inflammation in smokers, we will also determine whether functional single nucleotide polymorphisms in the LPS Receptor Complex are associated with serum levels of inflammatory markers (Specific Aim 2). Finally, the predicitve value of global protein expression profiles for COPD development will be explored using proteomic analyses (Specific Aim 3). To address these specific aims, we will use the large longitudinal population-based cohort of the TESAOD study, which was intitiated in 1972 and - over the 33-year follow-up period - has provided an enormous amount of phenotypic information and an extensive collection of prospective serum samples. The identification of systemic biomarkers linked to COPD development and its clinical progression may have important implications for the prevention and treatment of the disease. This study will lead to the establishment of a collaborative project between the molecular and genetic epidemiology core of the Arizona Respiratory Center and the Proteomics Analysis Laboratory at the University of Arizona and, in turn, it may foster the growth of a long-term research project to expand our understanding of the molecular components of COPD and to explore innovative strategies to reduce the morbidity and mortality of this disease. [unreadable] [unreadable] [unreadable]